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J. Biol. Chem., Vol. 282, Issue 49, 35757-35764, December 7, 2007

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Continuous Activation of G_q in Osteoblasts Results in Osteopenia through Impaired Osteoblast Differentiation^*

Naoshi Ogata, Hiroshi Kawaguchi¹, Ung-il Chung, Sanford I. Roth^¶, and Gino V. Segre

From the Endocrine Unit and ^¶Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114 and Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan

We explored the role of G_q-mediated signaling on skeletal homeostasis by selectively expressing a constitutively active G_q (mutation of Q209L) in osteoblasts. Continuous signaling via G_q in mouse osteoblastic MC3T3-E1 cells impaired differentiation. Mice that expressed the constitutively active G_q transgene in cells of the osteoblast lineage exhibited severe osteopenia in cortical and trabecular bones. Osteoblast number, bone volume, and trabecular thickness were reduced in transgenic mice, but the osteoclasts were unaffected. Osteoblasts from transgenic mice showed impaired differentiation and matrix formation. In the presence of a protein kinase C inhibitor GF109203X, this impairment was not seen, indicating mediation by the protein kinase C pathway. We propose that continuous activation of the G_q signal in osteoblasts plays a crucial, previously unrecognized role in bone formation.

Received for publication, December 29, 2006 , and in revised form, September 5, 2007.

^* This work was supported by National Institutes of Health Grants DK11794 and DK47034 (to G. V. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Sensory & Motor System Medicine, Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo, Tokyo 113-8655, Japan. Tel.: 81-33815-5411 (Ext. 30473); Fax: 81-33818-4082; E-mail: kawaguchi-ort{at}h.u-tokyo.ac.jp.

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